Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation- induced hepatic injury

Wen Hong Kan, Jun Te Hsu, Martin G. Schwacha, Mashkoor A. Choudhry, Raghavan Raju, Kirby I. Bland, Irshad H. Chaudry

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for ∼90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/ resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma α-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1α, ICAM-1, IL-6, TNF-α, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/ resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

Original languageEnglish (US)
Pages (from-to)1076-1082
Number of pages7
JournalJournal of Applied Physiology
Volume105
Issue number4
DOIs
StatePublished - Oct 2008

Keywords

  • Chemokine
  • Cytokine
  • Hypoxia-inducible factor-1α
  • Myeloperoxidase activity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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